When bone tissue is broken or otherwise damaged, bone-forming cells, called osteoblasts, proliferate and differentiate to regenerate bone. In the case of mild damage, fixation of the affected area helps osteoblasts function, leading to bone healing. In the case of compound fracture, intra-articular injury, concomitant osteomyelitis, etc., osteoblasts cannot effectively function and various surgical interventions, such as autologous bone grafting, implantation of artificial joints and artificial bones and injection of bone substitute materials, are applied. Recently, with the progress of aging, there is a growing demand for artificial bones and bone substitute materials which replace bone lost due to bone tumor excision, comminuted fracture, bone defect associated with arthrodesis in rheumatoid arthritis, alveolar ridge resorption, etc.
Currently, most of clinically-used artificial bones and bone substitute materials are composed of calcium phosphate, which is a bioactive, biocompatible and osteoconductive substance. Known calcium phosphate-based bone substitute materials include non-absorptive materials such as hydroxyapatite (Ca10(PO4)6 (OH)2) (Patent Literature 1 and 2) and absorptive materials such as β-tricalcium phosphate (β-TCP) (Patent Literature 3, 4, 5 and 6).
However, these biomaterials are inferior to autologous bones in osteoinductive activity etc. In addition, non-absorptive materials are not replaced with natural bone, thus causing problems in terms of bone strength and implant-bone integration (osseointegration) during and/or after healing. Absorptive materials are reduced in volume during the replacement with natural bone, thus causing problems in terms of bone morphology after healing. Therefore, the use of these materials in surgical intervention does not always lead to good prognosis.
Under such circumstances, there is a demand to promote the development of next-generation artificial bones and bone substitute materials which are a hybrid type of product having a combination of an artificial bone structure and a growth factor protein such as BMP (bone morphogenetic protein).
Meanwhile, “extracellular matrix”, which is a fibrous and net-like structure outside somatic cells, has been shown to be important for bone tissue regeneration (Non Patent Literature 1 and 2). In this view, a simple mixture of a calcium phosphate material with a growth factor can hardly provide satisfactory results in bone regeneration. Particularly in dentistry, the improvement of the outcome of implant treatment requires technologies for regenerating a vertical bone defect resulting from tooth loss, but vertical bone regeneration has not been achieved with the use of conventional bone substitute materials.
On the other hand, stem cell-based approaches in bone regenerative medicine are regarded as more effective than conventional bone regeneration technologies because the cells themselves produce extracellular matrices and growth factors (Non Patent Literature 3). Particularly, induced pluripotent stem cells (iPS cells), which were first established in Japan, are a type of stem cells that can be generated from patient's own cells without the destruction of fertilized eggs, which is essential for generating embryonic stem cells (ES cells), and thus are expected to be clinically applied. However, the biggest problem of the iPS cell-based treatment is the risk of neoplastic transformation of transplanted cells due to the use of living stem cells. Another problem is the need of large-scale equipment and facilities for cell culture.
Therefore, the development of novel stem cell-based therapies in bone regenerative medicine which are safe and highly therapeutically effective has been desired.